PMID- 25758528
OWN - NLM
STAT- MEDLINE
DCOM- 20160209
LR  - 20220409
IS  - 2041-1723 (Electronic)
IS  - 2041-1723 (Linking)
VI  - 6
DP  - 2015 Mar 11
TI  - RB loss in resistant EGFR mutant lung adenocarcinomas that transform to 
      small-cell lung cancer.
PG  - 6377
LID - 10.1038/ncomms7377 [doi]
LID - 6377
AB  - Tyrosine kinase inhibitors are effective treatments for non-small-cell lung 
      cancers (NSCLCs) with epidermal growth factor receptor (EGFR) mutations. However, 
      relapse typically occurs after an average of 1 year of continuous treatment. A 
      fundamental histological transformation from NSCLC to small-cell lung cancer 
      (SCLC) is observed in a subset of the resistant cancers, but the molecular 
      changes associated with this transformation remain unknown. Analysis of tumour 
      samples and cell lines derived from resistant EGFR mutant patients revealed that 
      Retinoblastoma (RB) is lost in 100% of these SCLC transformed cases, but rarely 
      in those that remain NSCLC. Further, increased neuroendocrine marker and 
      decreased EGFR expression as well as greater sensitivity to BCL2 family 
      inhibition are observed in resistant SCLC transformed cancers compared with 
      resistant NSCLCs. Together, these findings suggest that this subset of resistant 
      cancers ultimately adopt many of the molecular and phenotypic characteristics of 
      classical SCLC.
FAU - Niederst, Matthew J
AU  - Niederst MJ
AD  - 1] Massachusetts General Hospital Cancer Center, Massachusetts General Hospital, 
      55 Fruit Street, Boston, Massachusetts 02114, USA [2] Department of Medicine, 
      Harvard Medical School, 25 Shattuck Street, Boston, Massachusetts 02115, USA.
FAU - Sequist, Lecia V
AU  - Sequist LV
AD  - 1] Massachusetts General Hospital Cancer Center, Massachusetts General Hospital, 
      55 Fruit Street, Boston, Massachusetts 02114, USA [2] Department of Medicine, 
      Harvard Medical School, 25 Shattuck Street, Boston, Massachusetts 02115, USA.
FAU - Poirier, John T
AU  - Poirier JT
AD  - Memorial Sloan Kettering Cancer Center, Thoracic Oncology Service, 1275 York 
      Avenue, New York, New York 10065, USA.
FAU - Mermel, Craig H
AU  - Mermel CH
AD  - 1] Broad Institute of MIT and Harvard, Cancer Genome Comparative Analysis Group, 
      415 Main Street, Cambridge, Massachusetts 02142, USA [2] Department of Pathology, 
      Massachusetts General Hospital Cancer Center, 55 Fruit Street, Boston, 
      Massachusetts 02114, USA.
FAU - Lockerman, Elizabeth L
AU  - Lockerman EL
AD  - 1] Massachusetts General Hospital Cancer Center, Massachusetts General Hospital, 
      55 Fruit Street, Boston, Massachusetts 02114, USA [2] Department of Medicine, 
      Harvard Medical School, 25 Shattuck Street, Boston, Massachusetts 02115, USA.
FAU - Garcia, Angel R
AU  - Garcia AR
AD  - 1] Massachusetts General Hospital Cancer Center, Massachusetts General Hospital, 
      55 Fruit Street, Boston, Massachusetts 02114, USA [2] Department of Medicine, 
      Harvard Medical School, 25 Shattuck Street, Boston, Massachusetts 02115, USA.
FAU - Katayama, Ryohei
AU  - Katayama R
AD  - 1] Massachusetts General Hospital Cancer Center, Massachusetts General Hospital, 
      55 Fruit Street, Boston, Massachusetts 02114, USA [2] Department of Medicine, 
      Harvard Medical School, 25 Shattuck Street, Boston, Massachusetts 02115, USA.
FAU - Costa, Carlotta
AU  - Costa C
AD  - 1] Massachusetts General Hospital Cancer Center, Massachusetts General Hospital, 
      55 Fruit Street, Boston, Massachusetts 02114, USA [2] Department of Medicine, 
      Harvard Medical School, 25 Shattuck Street, Boston, Massachusetts 02115, USA.
FAU - Ross, Kenneth N
AU  - Ross KN
AD  - 1] Massachusetts General Hospital Cancer Center, Massachusetts General Hospital, 
      55 Fruit Street, Boston, Massachusetts 02114, USA [2] Department of Medicine, 
      Harvard Medical School, 25 Shattuck Street, Boston, Massachusetts 02115, USA.
FAU - Moran, Teresa
AU  - Moran T
AD  - 1] Massachusetts General Hospital Cancer Center, Massachusetts General Hospital, 
      55 Fruit Street, Boston, Massachusetts 02114, USA [2] Department of Medicine, 
      Harvard Medical School, 25 Shattuck Street, Boston, Massachusetts 02115, USA.
FAU - Howe, Emily
AU  - Howe E
AD  - 1] Massachusetts General Hospital Cancer Center, Massachusetts General Hospital, 
      55 Fruit Street, Boston, Massachusetts 02114, USA [2] Department of Medicine, 
      Harvard Medical School, 25 Shattuck Street, Boston, Massachusetts 02115, USA.
FAU - Fulton, Linnea E
AU  - Fulton LE
AD  - 1] Massachusetts General Hospital Cancer Center, Massachusetts General Hospital, 
      55 Fruit Street, Boston, Massachusetts 02114, USA [2] Department of Medicine, 
      Harvard Medical School, 25 Shattuck Street, Boston, Massachusetts 02115, USA.
FAU - Mulvey, Hillary E
AU  - Mulvey HE
AD  - 1] Massachusetts General Hospital Cancer Center, Massachusetts General Hospital, 
      55 Fruit Street, Boston, Massachusetts 02114, USA [2] Department of Medicine, 
      Harvard Medical School, 25 Shattuck Street, Boston, Massachusetts 02115, USA.
FAU - Bernardo, Lindsay A
AU  - Bernardo LA
AD  - 1] Department of Pathology, Massachusetts General Hospital Cancer Center, 55 
      Fruit Street, Boston, Massachusetts 02114, USA [2] Department of Pathology, 
      Harvard Medical School, 25 Shattuck Street, Boston, Massachusetts 02115, USA.
FAU - Mohamoud, Farhiya
AU  - Mohamoud F
AD  - 1] Massachusetts General Hospital Cancer Center, Massachusetts General Hospital, 
      55 Fruit Street, Boston, Massachusetts 02114, USA [2] Department of Medicine, 
      Harvard Medical School, 25 Shattuck Street, Boston, Massachusetts 02115, USA.
FAU - Miyoshi, Norikatsu
AU  - Miyoshi N
AD  - 1] Department of Medicine, Harvard Medical School, 25 Shattuck Street, Boston, 
      Massachusetts 02115, USA [2] Molecular Profiling Laboratory, Massachusetts 
      General Hospital Cancer Center, Massachusetts General Hospital, 55 Fruit Street, 
      Boston, Massachusetts 02114, USA.
FAU - VanderLaan, Paul A
AU  - VanderLaan PA
AD  - Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical 
      School, 330 Brookline Avenue, Boston, Massachusetts 02115, USA.
FAU - Costa, Daniel B
AU  - Costa DB
AD  - Department of Medicine, Division of Hematology/Oncology, Beth Israel Deaconess 
      Medical Center, Harvard Medical School, 330 Brookline Avenue, Boston, 
      Massachusetts 02115, USA.
FAU - Janne, Pasi A
AU  - Janne PA
AD  - 1] Department of Medical Oncology, Belfer Institute of Applied Science, Dana 
      Farber Cancer Institute, 450 Brookline Avenue, Boston, Massachusetts 02215, USA 
      [2] Department of Medicine, Brigham and Women's Hospital and Harvard Medical 
      School, 75 Francis Street, Boston, Massachusetts 02115, USA.
FAU - Borger, Darrell R
AU  - Borger DR
AD  - 1] Massachusetts General Hospital Cancer Center, Massachusetts General Hospital, 
      55 Fruit Street, Boston, Massachusetts 02114, USA [2] Department of Medicine, 
      Harvard Medical School, 25 Shattuck Street, Boston, Massachusetts 02115, USA.
FAU - Ramaswamy, Sridhar
AU  - Ramaswamy S
AD  - 1] Massachusetts General Hospital Cancer Center, Massachusetts General Hospital, 
      55 Fruit Street, Boston, Massachusetts 02114, USA [2] Department of Medicine, 
      Harvard Medical School, 25 Shattuck Street, Boston, Massachusetts 02115, USA [3] 
      Broad Institute of MIT and Harvard, Cancer Genome Comparative Analysis Group, 415 
      Main Street, Cambridge, Massachusetts 02142, USA.
FAU - Shioda, Toshi
AU  - Shioda T
AD  - 1] Department of Medicine, Harvard Medical School, 25 Shattuck Street, Boston, 
      Massachusetts 02115, USA [2] Molecular Profiling Laboratory, Massachusetts 
      General Hospital Cancer Center, Massachusetts General Hospital, 55 Fruit Street, 
      Boston, Massachusetts 02114, USA.
FAU - Iafrate, Anthony J
AU  - Iafrate AJ
AD  - 1] Department of Pathology, Massachusetts General Hospital Cancer Center, 55 
      Fruit Street, Boston, Massachusetts 02114, USA [2] Department of Pathology, 
      Harvard Medical School, 25 Shattuck Street, Boston, Massachusetts 02115, USA.
FAU - Getz, Gad
AU  - Getz G
AD  - 1] Department of Medicine, Harvard Medical School, 25 Shattuck Street, Boston, 
      Massachusetts 02115, USA [2] Broad Institute of MIT and Harvard, Cancer Genome 
      Comparative Analysis Group, 415 Main Street, Cambridge, Massachusetts 02142, USA 
      [3] Department of Pathology, Massachusetts General Hospital Cancer Center, 55 
      Fruit Street, Boston, Massachusetts 02114, USA.
FAU - Rudin, Charles M
AU  - Rudin CM
AD  - Memorial Sloan Kettering Cancer Center, Thoracic Oncology Service, 1275 York 
      Avenue, New York, New York 10065, USA.
FAU - Mino-Kenudson, Mari
AU  - Mino-Kenudson M
AD  - 1] Department of Pathology, Massachusetts General Hospital Cancer Center, 55 
      Fruit Street, Boston, Massachusetts 02114, USA [2] Department of Pathology, 
      Harvard Medical School, 25 Shattuck Street, Boston, Massachusetts 02115, USA.
FAU - Engelman, Jeffrey A
AU  - Engelman JA
AD  - 1] Massachusetts General Hospital Cancer Center, Massachusetts General Hospital, 
      55 Fruit Street, Boston, Massachusetts 02114, USA [2] Department of Medicine, 
      Harvard Medical School, 25 Shattuck Street, Boston, Massachusetts 02115, USA.
LA  - eng
SI  - GEO/GSE64322
SI  - GEO/GSE64765
SI  - GEO/GSE64766
GR  - P50CA090578/CA/NCI NIH HHS/United States
GR  - R01 CA137008/CA/NCI NIH HHS/United States
GR  - R01CA137008/CA/NCI NIH HHS/United States
GR  - P30 CA008748/CA/NCI NIH HHS/United States
GR  - P50 CA090578/CA/NCI NIH HHS/United States
GR  - R21 CA156000/CA/NCI NIH HHS/United States
GR  - 5R21CA156000/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, Non-P.H.S.
DEP - 20150311
PL  - England
TA  - Nat Commun
JT  - Nature communications
JID - 101528555
RN  - 0 (Aniline Compounds)
RN  - 0 (Antineoplastic Agents)
RN  - 0 (BCL2 protein, human)
RN  - 0 (BCL2L1 protein, human)
RN  - 0 (Protein Kinase Inhibitors)
RN  - 0 (Proto-Oncogene Proteins c-bcl-2)
RN  - 0 (Quinazolines)
RN  - 0 (Retinoblastoma Protein)
RN  - 0 (Sulfonamides)
RN  - 0 (bcl-X Protein)
RN  - 41UD74L59M (Afatinib)
RN  - DA87705X9K (Erlotinib Hydrochloride)
RN  - EC 2.7.10.1 (EGFR protein, human)
RN  - EC 2.7.10.1 (ErbB Receptors)
RN  - S65743JHBS (Gefitinib)
RN  - XKJ5VVK2WD (navitoclax)
SB  - IM
MH  - Adenocarcinoma/drug therapy/*genetics/metabolism/pathology
MH  - Adenocarcinoma of Lung
MH  - Afatinib
MH  - Aniline Compounds/pharmacology
MH  - Antineoplastic Agents/*pharmacology
MH  - Carcinoma, Non-Small-Cell Lung/drug therapy/*genetics/metabolism/pathology
MH  - Cell Line, Tumor
MH  - Disease Progression
MH  - Drug Resistance, Neoplasm/drug effects/genetics
MH  - ErbB Receptors/antagonists & inhibitors/deficiency/*genetics
MH  - Erlotinib Hydrochloride/pharmacology
MH  - Gefitinib
MH  - Gene Expression Regulation, Neoplastic
MH  - Humans
MH  - Lung/drug effects/metabolism/pathology
MH  - Lung Neoplasms/drug therapy/*genetics/metabolism/pathology
MH  - Mutation
MH  - Protein Kinase Inhibitors/*pharmacology
MH  - Proto-Oncogene Proteins c-bcl-2/genetics/metabolism
MH  - Quinazolines/pharmacology
MH  - Recurrence
MH  - Retinoblastoma Protein/deficiency/*genetics
MH  - Signal Transduction
MH  - Small Cell Lung Carcinoma/drug therapy/*genetics/metabolism/pathology
MH  - Sulfonamides/pharmacology
MH  - bcl-X Protein/genetics/metabolism
PMC - PMC4357281
MID - NIHMS657704
COIS- J.A.E. is a consultant for Novartis, Sanofi-Aventis, Genentech and Astra Zeneca; 
      owns equity in Gatekeeper Pharmaceuticals, which has interest in T790M 
      inhibitors; is a Scientific Advisory Board member for Sanofi-Aventis; has 
      research agreements with Novartis, Sanofi-Aventis and Astra Zeneca. A.J.I. is a 
      consultant for Pfizer and Bioreference Laboratories. P.A.J. is a consultant for 
      AstraZeneca, Boehringer Ingelheim, Chugai Pharma, Clovis, Genentech, Merrimack 
      Pharmaceuticals, Pfizer and Sanofi; owns stock in Gatekeeper Pharmaceutical; 
      receives other renumeration from LabCorp. C.M.R. has been a recent consultant for 
      AbbVie, Biodesix, Boehringer Ingelheim, Glaxo Smith Kline and Merck regarding 
      cancer drug development. The remaining authors declare no competing financial 
      interests.
EDAT- 2015/03/12 06:00
MHDA- 2016/02/10 06:00
PMCR- 2015/04/02
CRDT- 2015/03/12 06:00
PHST- 2014/04/27 00:00 [received]
PHST- 2015/01/21 00:00 [accepted]
PHST- 2015/03/12 06:00 [entrez]
PHST- 2015/03/12 06:00 [pubmed]
PHST- 2016/02/10 06:00 [medline]
PHST- 2015/04/02 00:00 [pmc-release]
AID - ncomms7377 [pii]
AID - 10.1038/ncomms7377 [doi]
PST - epublish
SO  - Nat Commun. 2015 Mar 11;6:6377. doi: 10.1038/ncomms7377.